Abstract

Background

Histone methyltransferase enhancer of zeste homologue 2 (EZH2) forms an obligate repressive
complex with suppressor of zeste 12 and embryonic ectoderm development, which is thought,
along with EZH1, to be primarily responsible for mediating Polycomb-dependent gene
silencing. Polycomb-mediated repression influences gene expression across the entire
gamut of biological processes, including development, differentiation and cellular
proliferation. Deregulation of EZH2 expression is implicated in numerous complex human
diseases. To date, most EZH2-mediated function has been primarily ascribed to a single
protein product of the EZH2 locus.

Results

We report that the EZH2 locus undergoes alternative splicing to yield at least two structurally and functionally
distinct EZH2 methyltransferases. The longest protein encoded by this locus is the
conventional enzyme, which we refer to as EZH2α, whereas EZH2β, characterized here,
represents a novel isoform. We find that EZH2β localizes to the cell nucleus, complexes
with embryonic ectoderm development and suppressor of zeste 12, trimethylates histone
3 at lysine 27, and mediates silencing of target promoters. At the cell biological
level, we find that increased EZH2β induces cell proliferation, demonstrating that
this protein is functional in the regulation of processes previously attributed to
EZH2α. Biochemically, through the use of genome-wide expression profiling, we demonstrate
that EZH2β governs a pattern of gene repression that is often ontologically redundant
from that of EZH2α, but also divergent for a wide variety of specific target genes.

Conclusions

Combined, these results demonstrate that an expanded repertoire of EZH2 writers can
modulate histone code instruction during histone 3 lysine 27-mediated gene silencing.
These data support the notion that the regulation of EZH2-mediated gene silencing
is more complex than previously anticipated and should guide the design and interpretation
of future studies aimed at understanding the biochemical and biological roles of this
important family of epigenomic regulators.